Real‐world first‐line treatment with pembrolizumab for non‐small cell lung carcinoma with high PD‐L1 expression: Updated analysis

Abstract Background Selecting pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum‐based chemotherapy (COMB) for patients with nonsmall cell lung cancer (NSCLC) and high programmed death‐ligand 1 (PD‐L1) expression is an important issue in clinical practice. We previously conducted a retrospective multicenter observational study of patients with NSCLC and high PD‐L1 expression who received MONO or COMB as a first‐line treatment. Here, we report updated data and evaluate the long‐term outcomes. Methods We performed a retrospective multicenter study of 298 patients with NSCLC and high PD‐L1 expression who received MONO or COMB as first‐line treatment between December 2018 and January 2020. We reviewed the medical records and assessed the clinical efficacy and toxicity using a prolonged data cutoff. Results In total, 164 (median age: 74 years) and 134 (median age: 68 years) patients received MONO and COMB, respectively; patients who received COMB were younger and had better performance statuses (0–1). At the prolonged data cutoff, the median follow‐up was 20.2 (range: 0.1–41.4) months. The median progression‐free survivals were 7.5 and 13.1 months, and overall survivals (OSs) were 17.2 and 33.7 months for MONO and COMB, respectively. Treatment discontinuation rates were 21.9% and 20.1% for the MONO and COMB, respectively. With prolonged follow‐up, although COMB demonstrated an OS benefit and higher objective response rate than MONO, in the propensity score matching analysis COMB didn't demonstrate a significant benefit compared to the MONO. Conclusions COMB may be effective as a first‐line treatment for NSCLC with high PD‐L1 expression in a selected subset of patients.


| INTRODUCTION
The efficacy of immune checkpoint inhibitors (ICIs) has recently been reported, emerging as a standard therapy for patients with advanced-stage nonsmall cell lung cancer (NSCLC).2][3][4][5] Conversely, a lower incidence of treatment-related adverse events (AEs) were reported in patients who received MONO compared with COMB.These results suggest that MONO and COMB are beneficial first-line treatments for advanced NSCLC with high PD-L1 expression, and that MONO is better tolerated than COMB.
Based on the limited data, selection between MONO and COMB for patients with NSCLC with high PD-L1 expression in the real world is important.We previously conducted a retrospective multicenter observational trial, Hokkaido Lung Cancer Clinical Study Group (HOT)/ North Japan Lung Cancer Study Group (NJLCG) 2001 (UMIN000040223), with a data cutoff date of August 31, 2020. 6The median PFSs were 7.1 months and 13.1 months in the MONO and COMB groups, respectively, which was significantly different.Additionally, the objective response rates (ORRs) were 41% and 67.4% in the MONO and COMB groups, respectively.The incidence of AEs of grade 3 or higher, or associated with treatment discontinuation, was similar in both groups.Our results suggested that COMB may be a promising first-line treatment for NSCLC with high PD-L1 expression and a good performance status (PS).8][9] However, these findings remain controversial, and it is unclear whether MONO or COMB is superior for patients with NSCLC and high PD-L1 expression in the real world.
Herein, we report the updated PFS, OS, ORR, 2-year survival rate, and safety data (additional 17-month follow-up for a median follow-up duration of 20.2 months) of 298 patients with NSCLC and high PD-L1 expression, who received MONO or COMB as a first-line treatment.We aimed to evaluate the long-term outcomes of patients in this setting, as well as conduct statistical analyses to support the selection of appropriate treatments in the real world.

| Study Design
The retrospective, multicenter, observational study (HOT/ NJLCG2001) design has been previously described [6].Eligible patients had previously untreated advanced NSCLC with a PD-L1 TPS of ≥50%, and no sensitizing EGFR, ALK, or ROS-1 alterations; additionally, they received MONO or COMB as the first-line treatment between December 2018 and January 2020.The efficacies and toxicities of MONO and COMB were also evaluated.We reviewed the medical records of 34 institutions of HOT, NJLCG, and Shinshu area institutions in Japan.This study was approved by the institutional review boards of all the institutions, which waived the need for informed consent owing to the anonymous nature of the data.The extended data cutoff date for this study was January 31, 2022.type of chemotherapy (carboplatin + pemetrexed, cisplatin + pemetrexed, carboplatin + nab-paclitaxel, and carboplatin + paclitaxel).We extracted AE types of grade 3 or higher, and AE types leading to treatment discontinuation using common terminology criteria for adverse events (CTCAE ver.5.0). 10 Tumor response was measured using the Response Evaluation Criteria in Solid tumors version 1.1 (RECIST 1.1), 11 and assessments were performed at each participating institution.

| Statistical analysis
Details were previously described. 6PFS was defined as the time interval between the initial treatment administration and disease progression or death; patients without documented clinical or radiographic disease progression or those who were still alive were censored on the date of the last follow-up.OS was defined as the time interval between initial treatment administration and any cause of death.PFS and OS were evaluated using the Kaplan-Meier method and compared using a two-sided log-rank test.To reduce selection bias and obtain similar comparison groups, we used a propensity score-matched pair method combined with covariate adjustment, with age and PS as adjustment factors, to analyze patients treated with MONO or COMB.Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards regression model.All p-values were two-sided, and the threshold for statistical significance was set at p < 0.05.All statistical analyses were performed using JMP Ver.13.2.0 (SAS Institute Inc., Cary, NC, USA).

| Patient characteristics
At the data cutoff date (August 31, 2020), a total of 300 patients with advanced NSCLC and a TPS ≥50% who underwent first-line treatment were enrolled in this study; two were excluded at the prolonged data cutoff date (January 31, 2022).Of the 298 patients, 164 (55%) and 134 (45%) received MONO and COMB, respectively (Figure 1).The baseline patient characteristics are summarized in Table 1.The median patient ages were 74 (range: 52-89) years and 68 (range: 45-84) years in the MONO and COMB groups, respectively.Patients in the COMB group were younger and had a better PS (0-1) (p < 0.01) (Table 1).

| Efficacy
At the prolonged data cutoff date (January 31, 2022), the median follow-up was 20.2 months (range: 0.1-41.4).The median PFSs were 7.5 months (95% CI: 6.2-12.1)and 13.1 months (95% CI:10.7-18.5) in the MONO and COMB groups, respectively (HR: 0.78; 95% CI: 0.59-1.03;p   2B).This analysis revealed an OS benefit for COMB in the total patient population.Next, we evaluated PFS and OS in selected PS and age subgroups.In the PS subgroup analysis, there were no statistically significant differences in PFS or OS between MONO and COMB treatments in the PS 0-1 subgroup (Figure 3A, B).However, the OS tended to be shorter with COMB than MONO in the PS 2-3 subgroup (PFS: 2.5 vs.  3C).In the age subgroups, the younger group (<75 years old) showed a trend toward better outcomes than the older group; however, there were no statistically significant   2).Additionally, the progressive disease rates were 28.7% (47/166) in the MONO group and 11.1% (15/134) in the COMB group (Table 2).

| Safety and toxicity
At the prolonged data cutoff date, 223 patients (74.8%) discontinued treatment.The treatment discontinuation rates were 82.9% (136/164) and 64.9% (87/134) in the MONO and COMB groups, respectively.Disease progression was the most common reason for treatment discontinuation; 40 (24.4%) and 34 (25.3%)patients in the MONO and COMB groups, respectively, discontinued treatment due to AEs.The AEs leading to discontinuation did not differ significantly between the MONO and COMB groups.The most frequently reported AE was pneumonitis, reported in 16 patients (9.6%) receiving MONO and 18 patients (13.4%) receiving COMB; all patients with pneumonitis discontinued treatment, including 12 patients (7.2%) in the MONO group and 11 (8.2%) in the COMB group with grade 3 pneumonitis (Table 3).No treatment-related deaths occurred in either group.

| Propensity score matching analysis
We used propensity score matching to adjust for factors that differed between the groups or were clinically important.Propensity score matching allowed the MONO and COMB scores to be almost identical regarding age and PS.To control for unbalanced conditions at the baseline between the two groups, 22 patients were excluded owing to a lack of detailed PD-L1 assessments.We used a propensity score-matched pairing method with age and PS as adjustment factors; 1:1 matching yielded matched pairs of 83 patients in both groups (Figure 1 and Table 4).In the matched cohort, the median PFS was 7.7 months (95% CI: 6.7-14.6) in the MONO group, and 10.9 months   5B).

| DISCUSSION
In this updated analysis, COMB continued to demonstrate an OS benefit and better ORR than MONO as a first-line therapy for advanced NSCLC with high PD-L1 expression.Discontinuation rates due to AEs were similar in both groups.However, there were no statistically significant differences in median OS between the COMB and MONO groups in the PSM analysis.Based on our results, although the COMB group did not show a statistically significant superiority compared to the MONO group in PSM, some patients may derive benefits from COMB depending on patient background factors such as PS and age.
Our study showed that COMB was associated with a longer OS and higher ORR than MONO (67.9% vs. 42.2%),and our results are consistent with those of several prospective studies and meta-analyses [1-4, 12].In another retrospective study, Chen et al. 7 reported that the PFS and OS of MONO and COMB were 9.6 and 12.4 (p Value <0.001), and 28.9 and NA (p Value = 0.005), respectively.By contrast, Dudhik et al. 8 observed no significant differences in long-term outcomes between MONO and COMB.In the real world, because large biases were observed in baseline characteristics such as  age and PS, which are often significantly related to the prognosis of patients, these results may be controversial.Additionally, at the prolonged data cutoff date, we evaluated the OS in subgroups by PS and age; in clinical practice, these are relevant to elucidate the treatment options for patients with a PS ≥2 who are aged ≥75 years.
In the subgroup analysis of PS, although there was no significant difference, the OS tended to be better with COMB than with MONO in the PS 0-1 group.In the age subgroups, the younger group (<75 years) showed a trend toward a better median OS with COMB than with MONO.Based on these results, background factors such as PS and age are important when selecting MONO or COMB, even in patients with high PD-L1 expression.
In the extended follow-up analysis, the proportion of patients experiencing AEs of grade 3 or higher, and AEs associated with treatment discontinuation, were similar; however, the incidence of AEs increased in both groups when compared with our previous report. 6Tang et al. 13 reported the pattern of time-to-onset of AEs caused by PD-1/ PD-L1 inhibitors.The pooled median time to onset of AEs of grade 3 or higher ranged from 14.1 weeks to 123.4 weeks for PD-1/PD-L1 inhibitors, and was significantly longer than that of all AEs.Although AEs generally occur within several months after the initiation of ICIs, they may appear several months or even years after completing treatment.Our updated analysis and this report suggest that the occurrence pattern and onset of AEs vary; thus, we should pay attention to AEs after the initiation and even completion of treatment.
PSM analysis demonstrated that the effect of chemotherapy on immunotherapy prolonged PFS by approximately 12 months, and reduced the rate of early exacerbation in COMB.Alternatively, immunotherapy may contribute to the long-term survival of patients with NSCLC.OS and 2-year survival rates were also similar after PSM in both groups.These results are consistent with those of previous reports, [12][13][14][15] suggesting that although the effect of immunotherapy on chemotherapy may be limited for patients with advanced NSCLC and high PD-L1 expression, COMB treatment should be considered as an option in cases of good PS.
This study had some limitations; first, this was a retrospective study, which may have led to a bias in regimen selection.However, we used PSM to reduce bias and compare the treatment efficacies of MONO and COMB.Second, the sample size was relatively small; however, because our data were similar to that of the meta-analysis, 12 our sample size reflects real-world data.Third, not all adverse events were recorded.Last, although we extended the observation period to obtain in-depth data on the long-term efficacy and safety, the duration was not sufficient.

| CONCLUSIONS
COMB continued to demonstrate an OS benefit and a higher ORR compared with MONO at longer follow-up but did not show a significant advantage over the MONO group in PSM analysis.Based on this extended real-world cohort, COMB continued to demonstrate an OS benefit and a higher ORR compared to MONO during longer follow-up.However, in PSM analysis, COMB did not show a significant advantage over the MONO group.Depending on patient characteristics such as age and PS, COMB may be effective as a first-line treatment for NSCLC with high PD-L1 expression in a selected subset of patients.

F I G U R E 1
As shown in the flowchart, 298 patients received either pembrolizumab monotherapy or pembrolizumab plus platinum-based chemotherapy between December 2018 and January 2020.We used the propensity score-matched pairing method, and 1:1 matching yielded 83 patient pairs.Patients with advanced NSCLC and high PD-L1 TPS (50%≤) received treatment for first line from December 2018 to January 2022.

F I G U R E 2
Kaplan-Meier curves of (A) progression-free survival and (B) overall survival of all patients receiving pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB).mo, month; OS, overall survival; PFS, progressionfree survival.F I G U R E 3 Kaplan-Meier curves of progression-free survival (PFS) and overall survival (OS) of all patients receiving pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) according to ECOG performance status.(A) PFS with PS 0-1, (B) PFS with PS ≥2, (C) OS with PS 0-1, (D) OS with PS ≥2.ECOG, Eastern Cooperative Oncology Group; mo, Month; PS, Performance status.

F I G U R E 4
Kaplan-Meier curves of progression-free survival (PS) and overall survival (OS) of patients receiving pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) according to age.(A) PFS of patients aged <75 years, (B) PFS of patients aged ≥75 years, (C) OS of patients aged <75 years, (D) OS of patients aged ≥75 years.mo, Month.T A B L E 2 Best tumor response to first line pembrolizumab monotherapy or pembrolizumab plus platinum-based chemotherapy.
Treatment-related adverse events (AEs) ≧grade 3 and leading to the discontinuation of all treatment.